Syntac polypeptides and uses thereof

Abstract

Methods and compositions for clonally inhibiting or clonally stimulating T-cells are provided.

1 .- 78 . (canceled) 
     
     
         79 . A multimeric polypeptide comprising:
 at least one heterodimer comprising:   a) a first polypeptide comprising:
 i) a peptide epitope; and 
 ii) first major histocompatibility complex (MHC) polypeptide; 
   b) a second polypeptide comprising a second MHC polypeptide, and   c) at least one immunomodulatory polypeptide   wherein the first and/or the second polypeptide comprises the immunomodulatory polypeptide, and   wherein the peptide epitope is an epitope present on a cancer cell.   
     
     
         80 . A multimeric polypeptide according to  claim 79 , wherein the first or the second polypeptide comprises an immunoglobulin (Ig) Fc polypeptide. 
     
     
         81 . A multimeric polypeptide according to  claim 80 , wherein the Ig Fc polypeptide is an IgG1 Fc polypeptide. 
     
     
         82 . A multimeric polypeptide according to  claim 79 , wherein:
 a) the first polypeptide comprises, in order from N-terminus to C-terminus:
 i) the peptide epitope; 
 ii) the first MHC polypeptide; and 
 iii) at least one immunomodulatory domain; and 
   b) the second polypeptide comprises, in order from N-terminus to C-terminus:
 i) the second MHC polypeptide; and 
 ii) an immunoglobulin (Ig) Fc polypeptide. 
   
     
     
         83 . A multimeric polypeptide according to  claim 79 , wherein:
 a) the first polypeptide comprises, in order from N-terminus to C-terminus:
 i) the peptide epitope; and 
 ii) the first MHC polypeptide; and 
   b) the second polypeptide comprises, in order from N-terminus to C-terminus:
 i) at least one immunomodulatory domain; 
 iii) the second MHC polypeptide; and 
 ii) an Ig Fc polypeptide. 
   
     
     
         84 . A multimeric polypeptide according to  claim 79 , wherein:
 a) the first polypeptide comprises, in order from N-terminus to C-terminus:
 i) the peptide epitope; and 
 ii) the first MHC polypeptide; and 
   b) the second polypeptide comprises, in order from N-terminus to C-terminus:
 i) the second MHC polypeptide; and 
 ii) the Ig Fc polypeptide; and 
 iii) at least one immunomodulatory domain. 
   
     
     
         85 . A multimeric polypeptide according to  claim 79 , wherein:
 a) the first polypeptide comprises, in order from N-terminus to C-terminus:
 i) the peptide epitope; and 
 ii) the first MHC polypeptide; and 
   b) the second polypeptide comprises, in order from N-terminus to C-terminus:
 i) the second MHC polypeptide; and 
 ii) at least one immunomodulatory domain. 
   
     
     
         86 . A multimeric polypeptide according to  claim 79 , wherein:
 a) the first polypeptide comprises, in order from N-terminus to C-terminus:
 i) the peptide epitope; and 
 ii) the first MHC polypeptide; and 
   b) a second polypeptide comprises, in order from N-terminus to C-terminus:
 i) at least one immunomodulatory domain; and 
 ii) the second MHC polypeptide. 
   
     
     
         87 . A multimeric polypeptide according to  claim 79 , wherein:
 a) the first polypeptide comprises, in order from N-terminus to C-terminus:
 i) the peptide epitope; 
 ii) the first MHC polypeptide; and 
 iii) at least one immunomodulatory domain; and 
   b) the second polypeptide comprises:
 i) the second MHC polypeptide. 
   
     
     
         88 . A multimeric polypeptide according to  claim 79 , wherein the first MHC polypeptide is a β2-microglobulin polypeptide; and wherein the second MHC polypeptide is an MHC class I heavy chain polypeptide. 
     
     
         89 . A multimeric polypeptide according to  claim 79 , wherein the at least one immunomodulatory polypeptide is selected from the group consisting of a cytokine, a 4-1BBL polypeptide, a B7-1 polypeptide; a B7-2 polypeptide, an ICOS-L polypeptide, an OX-40L polypeptide, a CD80 polypeptide, a CD86 polypeptide, a PD-L1 polypeptide, a FasL polypeptide, a PD-L2 polypeptide, and combinations thereof. 
     
     
         90 . A multimeric polypeptide according to  claim 89 , wherein the at least one immunomodulatory domain has a naturally occurring polypeptide sequence. 
     
     
         91 . A multimeric polypeptide according to  claim 89 , wherein the at least one immunomodulatory polypeptide comprises a cytokine. 
     
     
         92 . A multimeric polypeptide according to  claim 89 , wherein the multimeric polypeptide comprises at least two immunomodulatory polypeptides, and wherein at least two of the immunomodulatory polypeptides are the same. 
     
     
         93 . A multimeric polypeptide according to  claim 92 , wherein the 2 or more immunomodulatory polypeptides are in tandem. 
     
     
         94 . A multimeric polypeptide according to  claim 79 , wherein the first polypeptide and the second polypeptide are covalently linked. 
     
     
         95 . A multimeric polypeptide according to  claim 94 , wherein the covalent linkage is via a disulfide bond. 
     
     
         96 . A multimeric polypeptide according to  claim 95 , wherein the first MHC polypeptide or a linker between the epitope and the first MHC polypeptide comprises an amino acid substitution to provide a first Cys residue, and the second MHC polypeptide comprises an amino acid substitution to provide a second Cys residue, and wherein the disulfide linkage is between the first and the second Cys residues. 
     
     
         97 . A multimeric polypeptide according to  claim 79 , wherein the peptide epitope has a length of from about 4 amino acids to about 25 amino acids. 
     
     
         98 . A multimeric polypeptide according to  claim 79 , wherein the first polypeptide comprises a linker between the peptide epitope and the first MHC polypeptide. 
     
     
         99 . A multimeric polypeptide according to  claim 79 , wherein the first polypeptide comprises a linker between the first MHC polypeptide and the immunomodulatory polypeptide. 
     
     
         100 . A multimeric polypeptide according to  claim 98 , wherein the linker comprises a serine and a glycine. 
     
     
         101 . A multimeric polypeptide according to  claim 99 , wherein the linker comprises a serine and a glycine. 
     
     
         102 . A multimeric polypeptide according to  claim 80 , wherein the multimeric polypeptide comprises a first and a second heterodimer, and
 wherein the first and second heterodimers are covalently bound by one or more disulfide bonds between the Ig Fc polypeptides of the first and second heterodimers.   
     
     
         103 . A nucleic acid comprising a nucleotide sequence encoding a first or second polypeptide according to  claim 79 , wherein the first or second polypeptide comprises at least one immunomodulatory domain. 
     
     
         104 . A nucleic acid according to  claim 103 , wherein the multimeric polypeptide comprises a first and a second heterodimer, and
 wherein the first and second heterodimers are covalently bound by one or more disulfide bonds between the Ig Fc polypeptides of the first and second heterodimers.   
     
     
         105 . A method of selectively modulating the activity of an epitope-specific T cell, the method comprising contacting the T cell with a multimeric polypeptide according to  claim 79 , wherein said contacting selectively modulates the activity of the epitope-specific T cell. 
     
     
         106 . A method of selectively modulating the activity of an epitope-specific T cell according to  claim 105 , wherein the multimeric polypeptide comprises a first and a second heterodimer, and
 wherein the first and second heterodimers are covalently bound by one or more disulfide bonds between the Ig Fc polypeptides of the first and second heterodimers.   
     
     
         107 . A method of treating a patient having a cancer comprising administering to the patient an effective amount of a pharmaceutical composition comprising a multimeric polypeptide according to  claim 79 . 
     
     
         108 . A method of treating a patient having a cancer according to  claim 107 , herein the multimeric polypeptide comprises a first and a second heterodimer, and
 wherein the first and second heterodimers are covalently bound by one or more disulfide bonds between the Ig Fc polypeptides of the first and second heterodimers.